Depression as a co-morbidity is a barrier to achieving positive outcomes, improving quality of life, and delivering high-quality cancer and other care experiences. New onset depression in patients being treated for head and neck cancer is highly prevalent and leads to many negative health outcomes. Ketamine has been shown to have a rapid effect for treating depression, including in our own work in patients with cancer who were receiving hospice care. The goal of this innovative exploratory (R21) proposal is test the feasibility, safety, and tolerability of using ketamine for indicated prevention of depression in patients with head and neck cancer. We have chosen ketamine for its potential multiple positive attributes for patients with head/neck cancer: known rapid onset of action, proven efficacy in cancer pain, multiple routes of administration, ability to treat depression, and impact on co-morbid anxiety, all of which should lead to improved outcomes, including longevity and quality of life. Given the high proportion of patients with head and neck cancer who develop depression during treatment, the negative impacts that depression has on outcomes in these patients, and previous prevention trials in this population, head/neck cancer patients appear to be a good logical first choice to test ketamine's ability to prevent depression in these and other cancer patients. It is hoped that the outcomes of this proposal will lead to a definitive trial (R01 proposal) of ketamine for preventing depression in patients with head and neck cancer, with the ultimate goal of preventing depression and improving health outcomes in this, and possibly other, cancer populations. This proposal is consistent with the National Cancer Institute's research focus on co-morbidities, of which depression is likely one of the most impactful. It is also consistent with the NIH agenda of improving health outcomes. Specific Aim 1: Feasibility. To investigate the feasibility of enrolling subjects in a indicated prevention trial of oral ketamie vs placebo in patients receiving usual cancer care and treatment for stage III or IV epidermoid head/neck cancer. Hypothesis 1: At least 40 subjects will be enrolled and 80% of patients randomized will complete the trial. Specific Aim 2: Tolerability and Safety. To investigate the safety and tolerability of oral ketamine in patients receiving usual cancer care and treatment for stage III or IV epidermoid head/neck cancer. Hypothesis 2: Less than 20% of patients randomized to oral ketamine will drop-out due to adverse or serious adverse events attributed to ketamine, a proportion comparable to that in the placebo group. Exploratory Aims: Other data collected in this study will be used to explore ketamine's impact on: 1) incidence of depression, 2) anxiety symptoms, 3) pain levels, and 4) quality of life. Future Directions: This study will lay the groundwork for a larger, definitive trial (R01 proposal) of ketamine for the prevention of depression in patients with head and neck, and possibly other cancers. In the future, we may be able to explore further questions that may be of import for the prevention and/or relief of depression, suffering, and promotion of quality of life for cancer patients.